TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo

  • Nat Commun. 2024 Feb 14;15(1):1348. doi: 10.1038/s41467-024-45555-x.
Jinhee Kim  1 ,  Deepanwita Bose  #  2 ,  Mariluz Araínga  #  2 ,  Muhammad R Haque  3 ,  Christine M Fennessey  4 ,  Rachel A Caddell  5 ,  Yanique Thomas  3 ,  Douglas E Ferrell  2 ,  Syed Ali  2 ,  Emanuelle Grody  3  6 ,  Yogesh Goyal  3  6  7 ,  Claudia Cicala  8 ,  James Arthos  8 ,  Brandon F Keele  4 ,  Monica Vaccari  5  9 ,  Ramon Lorenzo-Redondo  1  10 ,  Thomas J Hope  3 ,  Francois Villinger  2 ,  Elena Martinelli  11
Affiliations
  • 1. Department of Medicine, Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 2. New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, USA.
  • 3. Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 4. AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 5. Division of Immunology, Tulane National Primate Research Center, Covington, LA, USA.
  • 6. Center for Synthetic Biology, Northwestern University, Chicago, IL, USA.
  • 7. Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 8. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 9. Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA.
  • 10. Center for Pathogen Genomics and Microbial Evolution, Northwestern University Havey Institute for Global Health, Chicago, IL, USA.
  • 11. Department of Medicine, Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected].
  • # Contributed equally.
PMID: 38355731 DOI: 10.1038/s41467-024-45555-x
Abstract

HIV-1 persistence during ART is due to the establishment of long-lived viral reservoirs in resting immune cells. Using an NHP model of barcoded SIVmac239 intravenous Infection and therapeutic dosing of anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirm the latency reversal properties of in vivo TGF-β blockade, decrease viral reservoirs and stimulate immune responses. Treatment of eight female, SIV-infected macaques on ART with four 2-weeks cycles of galunisertib leads to viral reactivation as indicated by plasma viral load and immunoPET/CT with a 64Cu-DOTA-F(ab')2-p7D3-probe. Post-galunisertib, lymph nodes, gut and PBMC exhibit lower cell-associated (CA-)SIV DNA and lower intact pro-virus (PBMC). Galunisertib does not lead to systemic increase in inflammatory cytokines. High-dimensional cytometry, bulk, and single-cell (sc)RNAseq reveal a galunisertib-driven shift toward an effector phenotype in T and NK cells characterized by a progressive downregulation in TCF1. In summary, we demonstrate that galunisertib, a clinical stage TGF-β inhibitor, reverses SIV latency and decreases SIV reservoirs by driving T cells toward an effector phenotype, enhancing immune responses in vivo in absence of toxicity.

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